Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers.

Yumeng Wang, Xiaoyan Xu, Shuangxing Yu, Kang Jin Jeong, Zhicheng Zhou, Leng Han, Yiu Huen Tsang, Jun Li, Hu Chen, Lingegowda S Mangala, Yuan Yuan, A Karina Eterovic, Yiling Lu, Anil K Sood, Kenneth L Scott, Gordon B Mills, Han Liang

Journal: Genome research 2018;27(7):1112-1125

PMID: 28411194

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Abstract

RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to the pattern observed for the wild-type miR-200b expression. We further experimentally showed that, in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit and acquired concomitant ability to repress new targets, including , a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.

Address: Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Pathophysiology, College of Basic Medicine Science, China Medical University, Shenyang, Liaoning Province 110122, China.; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, Texas 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

DOI: 10.1101/gr.219741.116